Outer retinal features in OCT predict visual recovery after primary macula-involving retinal detachment repair

Purpose To find predictive markers for the visual potential in optical coherence tomography (OCT) one month after surgical repair of macula-involving rhegmatogenous retinal detachment (miRD) with and without internal limiting membrane (ILM) peeling. Methods This retrospective single-center, single-surgeon cohort study included 74 patients who underwent pars plana vitrectomy (PPV) for primary miRD between January 2013 and August 2020 with follow-up examinations for at least 6 months. Patients developing recurrent detachments, media opacities, or with an axial length over 27 mm were excluded from the analysis. LogMAR visual (VA) and LogRAD reading acuity (RA) ± standard deviation (SD), and OCT measurements 6 months after surgery were compared to OCT and VA measurements one month after surgery using multiple linear regression analysis for predictions. Results VA increased from 0.34 ± 0.25 at one month to 0.22 ± 0.21 after 6 months [p < 0.001; effect size = -0.662, 95% confidence interval (CI): -(0.99–0.33)]. The continuity of the external limiting membrane (ELM) and ellipsoid zone (EZ) increased between 1 and 6 months. Subfoveal ELM integrity after one month predicted VA [adjusted R2 of 8.0%, F(2, 71) = 4.17, p = 0.018] and RA [adjusted R2 of 29%, F(2, 27) = 6.81, p = 0.002] after 6 months. EZ integrity had a less pronounced predictive effect on VA and RA. ELM integrity after 1 month correlated with better reading acuity after 6 months (p = 0.016). Conclusion VA and morphological OCT parameters improve between 1 and 6 months after surgery for miRD. The grade of ELM is a better predictor for RA than for VA, explaining more variance.

Introduction Macula-involving rhegmatogenous retinal detachment (miRD) is accompanied by a significant risk of permanent vision loss despite successful re-attachment surgery. Preoperative vision, duration of vision loss, and number of retinal breaks have been reported as preoperative factors associated with the postoperative visual potential, but published data are contradictory for some of these factors [1,2]. Preoperative features of optical coherence tomography (OCT) such as photoreceptor length, height of foveal detachment, inner retinal undulation and inner retinal separations have been discussed as biomarkers of visual recovery [3,4]. In cases of foveal detachment, visual recovery seems better if the macula is only partially detached, compared to a complete macular detachment [5]. Moreover, a preserved foveal depression despite foveal detachment seems predictive of a better functional outcome [6]. The optimal timing and technique of surgery are subject to discussion, and peeling of the internal limiting membrane (ILM) has been discussed as a potential factor for improved postoperative visual recovery, with evidence being still unclear [7][8][9][10]. A meta-analysis of available retrospective studies did not unequivocally support this finding [11]. A structural correlation of the fovea and visual recovery after vitrectomy has not been made to date.
The initial aim of this retrospective study was to compare ILM peeling to no ILM peeling, together with predictive imaging parameters in early postoperative OCT after 1 month. Due to high subgroup imbalance with few and biased cases without ILM peeling, we focused on early postoperative predictive biomarkers. The aim of this retrospective study was therefore to test a possible correlation of the aforementioned pre-and early postoperative features with the visual outcome after 6 months, and to compare both the postoperative OCT features and the visual recovery after successful re-attachment surgery.

Patients and methods
This retrospective study draws on consecutive data from patients undergoing surgical retinal detachment repair who were treated within 48 hours of referral at our institution by a single surgeon between January 2013 and August 2020. The study followed the tenets of the Declaration of Helsinki and was approved by the local ethical committee (BASEC-ID 2020-02920), with informed consent for analysis and publication of data from all patients. Inclusion criteria were primary rhegmatogenous retinal detachment with macular involvement (miRD), treated with pars plana vitrectomy, endodrainage, endolaser, and gas tamponade. Exclusion criteria were a postoperative follow-up of under 6 months, use of another tamponade, i.e. silicone oil, recurrent retinal detachment and/or any ocular surgery within the follow-up period of 6 months, cataract with significant visual impairment (if not treated during re-attachment surgery), age under 18 years at time of surgery, an axial length longer than 27 mm, active systemic and ocular inflammatory and vascular diseases requiring treatment (i.e. active rheumatological and metabolic diseases including diabetes, uveitis and retinal vascular occlusion), and finally, denial of informed consent. In patients with retinal detachment in both eyes, only the firstaffected eye was included.
Data were collected retrospectively from the electronic patient records at baseline before surgery (BL), and 1 month, 6 months, and where available 12 months after surgery. This included best corrected visual acuity (BCVA) using Snellen decimal charts, reading acuity (RA), axial length, duration of visual impairment, and optical coherence tomography (OCT; Heidelberg Spectralis spectral-domain OCT with 880 nm wavelength, with axial resolution of 3.9 μm and lateral resolution of 5.7 μm, Heidelberg Engineering, Heidelberg, Germany). Assessment of OCT included preoperative presence of outer retinal separation and undulation, foveal height of retinal detachment as the height of the subfoveal space, and photoreceptor outer segment thickness. One, 6, and 12 months after surgery, BCVA as well as OCT data were recorded. OCT assessments included manual grading of inner and outer retinal thickness, and inner and outer photoreceptor segment thickness, as well as outer photoreceptor segment thickness of the other eye.
Measurements of the OCT images were performed on the central horizontal B-scan at the foveal pit. Measurements of inner (IS) and outer (OS) photoreceptor segments, as well as inner (IR) and outer (OR) retinal height were assessed in the central fovea (Fig 1). The continuity of the external limiting membrane (ELM) and the ellipsoid zone (EZ) under the foveal pit were graded from one to four: 1 normal and continuous, 2 altered but continuous, 3 interrupted but recognizable, and 4 not recognizable (Fig 2). At baseline, wherever OCT was available, foveal detachment height was measured from the retinal pigment epithelium to the outer border of the retina, and presence or absence of retinal separation and undulation was assessed.
Data collection and OCT measurements were performed in a non-blinded manner by a single author (SL) and verified by another author (CH). Statistical analysis was performed using R (R Core Team, 2021. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/). For statistical purposes, BCVA was converted to the logarithm of the minimum angle of resolution (LogMAR), RA was converted to the logarithm of the reading acuity determination (LogRAD). All values are reported as mean with standard deviation (SD) as well as median and interquartile range (IQR). Changes over time are analyzed using one-way repeated measurements ANOVA for normally distributed data or the Friedman test for related data in cases where the data were not normally distributed. Significance was set at p < 0.05, and reported with effect sizes as well as lower and upper 95% confidence intervals (CI). The relationship between measurements was evaluated using multiple regression. Independence of observations was tested by applying the Durbin-Watson statistic.

Functional outcomes
Of a total of 406 surgeries for retinal detachment in the index period, 317 showed macular involvement, 228 were treated with PPV and sulfur hexafluoride (SF6) gas, and one each with perfluoropropane (C3F8) and air tamponade. Sixty patients (26%) had to be excluded due to re-detachment within 6 months. Of the remaining 168 eyes, only 74 were included in the analysis, mainly due to loss of follow-up (n = 50), with the complete list of reasons shown in Fig 3. Of the 74 included eyes, 68 (92%) underwent ILM peeling, and six (8%) did not. Twenty-two patients (30%) were female, and the mean age of the patients was 65.4 ± 10.1 years. Complete foveal detachment was present in 64 eyes (86.5%) from the included sample. The number of patients without complete foveal detachment (13.5%) was too small to allow a statistical comparison between patients with and without this condition regarding visual acuity and its development over time. Furthermore, these subgroups show different baseline characteristics, introducing relevant bias into the comparison. Reading acuity. Reading acuity (RA) measurements were available for only 11 patients at baseline, and 29 eyes after 1, and 30 eyes after 6 months. Since the amount of available data at baseline was small and biased towards better results, we refrain from making any statements about this time point. Reading acuity increased from 1 month (mean 0.48 LogRAD, SD ±0.21,

Morphological outcomes
Morphological parameters in the central OCT B-Scan were measured for inner retina, outer retina, and the inner and outer segments of the photoreceptors (together forming the outer retina). Recovery of the foveal structure can be observed visually (Fig 6).  Fig 8).

Multiple linear regressions for predictive factors for visual recovery
Multiple linear regression models were used to VA (n = 74) and RA (n = 29) after six months as dependent variables. As independent variables and predictors we used only morphological parameters for model 1 and morphological and functional parameters for model 2 (Table 1).
Model 1 included ELM and EZ grade after 1 month. Model 2 included VA after one months, and for prediction of RA, also RA after 1 month.
In the models analyzing effects on VA after 6 months (n = 74), we see a small yet significant effect of ELM grade after 1 month in predicting final VA [adjusted R 2 of 8.0%, F(2, 271 = 4.17, p = 0.018), if only morphological parameters are used. With the inclusion of VA after 1 month, the model's total adjusted R 2 achieved a medium effect of 52%, achieving statistical significance (p = 0.017). In the models analyzing effects on RA after 6 months (n = 29), we see a significant medium-size effect of ELM grade after 1 month in predicting final RA [adjusted R 2 of 29%, F (2, 27) = 6.81, p = 0.002], if only morphological parameters were used. With the inclusion of  months after vitrectomy with gas endotamponade for macula-involving primary retinal detachment. A slight but significant decrease in IR and increase in OR were seen. Mean IR thickness decreased from 219.7 ± 79.8 μm to 206.2 ± 57.6 μm, and OR increased from 75.3 ± 19.5 μm to 83.9 ± 11.8 μm (Friedman test for correlated samples p = 0.014 for IR, and p = 0.0005 for OR, n = 74 at 1 month and n = 73 at 6 months). Whiskers indicate standard deviations, and asterisks ( � ) indicate significant differences compared to 1 month (p < 0.01).
https://doi.org/10.1371/journal.pone.0268028.g007 VA and RA after 1 month, the model's total adjusted R 2 was 44%, without individual statistical significance for the included values. In other words, 8% of the variance in VA is predicted by ELM and EZ grade 1 month postoperatively (p = 0.019), and to 52% if VA was also included (p < 0.0001). Reading acuity after 6 months is explained to 29% by grade of ELM and EZ at 1 month (p = 0.004), and to 44% if VA and RA are also included.
When corrected for age, gender, ILM peeling, or presence of foveal detachment, the overall models including one-month grades of ELM with or without VA and RA remained statistically significant for both final VA and RA (S3 Table).
Separate analyses were performed with a simplified ELM grading into continuous (grades 1 and 2) or interrupted ELM (grades 3 and 4). The analyses revealed no predictive value of ELM integrity (grades 1-2 versus grades 3-4 taken together) on better or worse VA after 6 months (p = 0.51, n = 74). ELM integrity, however, correlated with RA after 6 months (p = 0.016, n = 29). Thus, ELM grades 1 or 2 demonstrated a better RA after 6 months compared to grades 3 or 4.
Furthermore, multiple regression models were developed using one-month measurements of photoreceptor inner (IS) and outer (OS) segment height with VA and RA at 6 months as dependent variables (S3 Table). Photoreceptor IS and OS had an adjusted R 2 of 8% on final VA (p = 0.024), and of 15% on final RA (p = 0.04). A composite model of presence of foveal detachment, detachment height, retinal separation and undulations before surgery did not yield significance on final VA or RA.

Discussion
Our results demonstrate that ELM is a better predictor of RA than VA, explaining more variance. ELM grade was able to explain 8% of the variance in VA compared to 29% in RA after 6 months. Also, a continuous ELM after 1 month is correlated with better RA after 6 months, compared with an interrupted ELM. While VA after 1 month could predict VA after 6 months, RA failed to predict either VA or RA after 6 months.
Our results demonstrate a surprisingly good overall visual outcome, with a mean BCVA of 0.22 LogMAR (20/33 Snellen equivalent) and 75% of patients below 0.3 LogMAR (better than 20/40 Snellen equivalent) 6 months after retinal detachment with macular involvement. We found a primary anatomical success rate of 74.7% in the group treated with SF6 (one each with C3F8 and air) gas tamponade, and of 81.1% in the group overall. In the underlying dataset, we used gas tamponade in 71.9% of 317 patients with macula-involving retinal detachment due to our policy of using gas endotamponade over silicone oil whenever possible, to avoid siliconeoil associated visual deteriorations. All surgical endpoints are within the range of published data, on the better side for visual function and on the poorer side for primary surgical success after 6 months, compared to studies combining vitrectomy and buckling surgery [12][13][14][15][16].  A gradual increase of visual and reading acuity from 1 to 6 months after surgery was linked to a qualitative morphological improvement of ELM and EZ in OCT B-Scan images, as well as a decrease in inner retinal thickness and an increase in outer retinal thickness. These findings are in accordance with previously published results, describing similar visual recovery and morphological retinal layer changes for up to 12 months with the major improvements occurring in the first 6 months [17][18][19]. On the other hand, we did not find distinct changes in outer photoreceptor segment length or inner/outer segment ratio.
The ELM grade, as the strongest and most consistent morphological predictor of final visual and reading acuity, can be quickly assessed from a single central B-Scan OCT, without the need for measurements of photoreceptor height or the memorization of normal ranges. The integrity of the ELM (grade 1 or 2 after 1 month) may thus be used as a rapidly assessable OCT biomarker for favorable reading acuity after 6 months, compared to cases with interrupted ELM (grades 3 or 4 1 month postoperatively).

Limitations
The main limitations of our study include its retrospective nature and the limited sample size; both are within the range of the existing literature, but may biasing to some extent the quantitative outcomes reported, if not the qualitative ones. Our OCT measurements are limited to the central transfoveal B-Scan, and performed manually in a non-blinded manner. Grading of ELM and EZ seems simple and straightforward, but may be subject to a degree of inter-and intra-rater variability. We addressed this using a seniority-based voting system for all ambiguous OCT parameters. Transverse imaging of ELM and EZ for quantifiable analysis, as has been used in age related macular degeneration [20], was not feasible in our retrospective data set, as the scan distance was too wide to reconstruct transverse imaging.
The majority of our patients (87%) received ILM peeling, which makes it impossible to compare the ILM peeling group with the non-peeling group. This bias is explained by the personal experience of our surgeon (JGG), with improved visual outcomes after ILM peeling [7,9]. A minority (14%) of patients showed an attached foveal center, with better functional prognosis. Functional parameters of the respective subgroups are presented in the supplementary material (S1 and S2 Tables). The comparison showed systematic bias towards less ILM peeling in the attached fovea group, and vice versa with better baseline VA. Thus, a subgroup analysis was not appropriate for these data, which was the primary intention of the study. The sample without peeling was too small to allow us to make meaningful statements about the differences between the groups with and without peeling. Henceforth, we describe the pooled data of both groups. A structural correlation between the fovea and visual recovery after vitrectomy with or without ILM peeling has not been made to date. The decision to analyze the pooled data is based on current evidence that neither a previous meta-analysis [11] nor a more recent retrospective study [8] could validate differences in functional or morphological outcomes between eyes with or without ILM peeling. Based on our primary study intention, we also included patients without peeling and pooled the results, though this may bias towards better final visual function and lesser functional improvement due to better visual function at baseline. Whether our findings can be applied on patients without ILM peeling remains unclear. Structural changes related to ILM peeling have been shown after retinal detachment surgery [21]. Our study cannot answer whether the observed structural changes in our cohort are due to the retinal detachment or the ILM peeling, which may longitudinally alter structure and thickness. Further limitations are the high drop-out rate of two-thirds of the possible cases due to loss of follow-up (38.6% of 228 patients), which is explained by the nature of the retrospective design and the referral structure at our clinic.
Our data could not detect prognostic effects of preoperative parameters such as foveal height of detachment, degrees of macular areas detached, shorter duration of macular detachment or visual loss until surgery, as is commonly established [1,5,6,22,23]. The subgroup without foveal detachment shows better baseline and final visual acuity, in accordance with these reports, but our subgroups were too small to make a statistical conclusion (S2 Table).

Conclusion
In conclusion, we found a strong predictive power of one-month morphological and functional findings, namely the ELM integrity and ELM grade, for the final distance and reading visual acuity after 6 months. The technically simple qualitative assessment of the ELM state 1 month after retinal detachment surgery is able to predict the near and distance visual potential and may thus serve as an OCT biomarker in macula-involving RD, explaining 8% of the variability in distance and 29% in near VA after 6 months. While the prediction of final visual function from exams after 1 month remains difficult, a better state of the ELM after 1 month may indicate favorable final VA outcome, and ELM integrity may indicate favorable final RA.